Combined treatment of acute EAE in Lewis rats with TNF-binding protein and interleukin-1 receptor antagonist.

Experimental autoimmune encephalomyelitis (EAE) is a term given to describe a collection of animal models representing the human disease multiple sclerosis (MS). Although not fully understood, the involvement of cytokines and the immune system in either EAE or human MS is well established. Past efforts have shown that inhibition of proinflammatory cytokines tumor necrosis factor (TNF-alpha) or interleukin-1 (IL-1) result in amelioration of acute EAE in Lewis rats. The present study examined this model for the effect of concomitant inhibition of both TNF-alpha and IL-1, which resulted in a modest but significant therapeutic effect that was superior to inhibition of either single agent alone with respect to four of the five variables used to follow the progression of disease in this model, i.e., clinical severity, frequency of disease, loss of body weight, and day of onset. These results are in accordance with the idea that combination treatments are likely to prove superior to single agent therapy in the treatment of autoimmune inflammatory disease.

Effect of zimeldine and its metabolites on [3H]thymidine incorporation in lymphocyte cultures from psychiatric patients with or without a hypersensitivity reaction during zimeldine therapy.

Lymphocyte transformation test (LTT) was applied to 28 patients who had developed a hypersensitivity syndrome (HSS) during treatment with the antidepressant drug zimeldine. Twenty-seven patients treated with zimeldine without any symptom of an HSS were matched controls. Zimeldine and its metabolites norzimeldine and CPP 200 all induced statistically significant increased [3H]thymidine incorporation in cultured lymphocytes from the HSS patients compared with the controls, norzimeldine being the most potent inducer. The results indicate an immunoreactive process in the development of the HSS induced by zimeldine.

Interaction study between remoxipride and biperiden.

Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin Cmax and tmax following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant (P = 0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction.

Neuroendocrine responses to single oral doses of remoxipride and sulpiride in healthy female and male volunteers.

Six female and six male healthy volunteers received 100 mg remoxipride, 200 mg sulpiride and placebo as single oral doses in a double blind trial with a randomized crossover design. The main objective was to compare the effect of the two drugs on serum prolactin levels, but effects on other hormones were also investigated. Remoxipride and sulpiride increased the serum levels of prolactin to similar peak levels. This effect was larger in female than in male subjects. Sulpiride increased prolactin levels at much lower plasma concentrations than remoxipride, and sulpiride's effect on prolactin lasted for considerably longer than remoxipride's. No consistent effects on serum levels of LH, FSH, GH, oestradiol, progesterone, testosterone or cortisol could be detected after remoxipride and sulpiride compared to placebo. No drug-related effects on plasma homovanillic acid (HVA) were found.

Drug interaction studies with remoxipride.

The interaction potential of remoxipride was investigated with biperiden, warfarin, diazepam, and ethanol. The studies were conducted in 12 healthy volunteers each of whom received single doses of remoxipride, the interacting drug, and the combination in a randomized crossover design. Remoxipride and biperidene had no influence on each other's pharmacokinetics. The pharmacokinetics of warfarin enantiomers were uninfluenced by remoxipride. Ethanol and diazepam had no effect on the pharmacokinetics of remoxipride. The effect of remoxipride on the elevation of plasma prolactin levels was not modified by biperiden and the effect of warfarin on the prolongation of prothrombin time was uninfluened by remoxipride. Remoxipride showed no pharmacokinetic interaction with any of the drugs studied, nor was any pharmacodynamic interaction observed in the remoxipride versus biperiden and remoxipride versus warfarin studies.

Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection.

To investigate the pharmacokinetics and effects of intravenous foscarnet, 13 relatively healthy male patients with human immunodeficiency virus infection and a mean CD4+ lymphocyte value of 0.45 x 10(-9) cells per liter were given a continuous intravenous infusion of foscarnet (0.14 to 0.19 mg/kg per min) for 8 to 21 days. Blood and urine samples were taken during and after drug administration to monitor foscarnet concentrations. Lumbar puncture was performed during the infusion in five patients. The concentrations in plasma showed large variations both within and between patients. The disposition of foscarnet could be explained by a triexponential equation (t1/2 lambda 1, 0.40 to 2.52 h; t1/2 lambda 2, 3.20 to 16.7 h; t1/2 lambda 3, 36 to 196 h). Renal clearance accounted for most of the plasma clearance, the difference probably reflecting the passage of foscarnet into bone. Up to 20% of the cumulative dose may have been deposited in bone 7 days postinfusion. Foscarnet was distributed to the cerebrospinal fluid in a concentration varying from 13 to 68% of the simultaneous concentration in plasma. Polyuria and polydipsia were recorded in all patients. There appears to be an association between the degree of malaise, including symptoms such as nausea, vomiting, fatigue, and headache, and concentrations in plasma above 350 mumol/liter.

Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus.

Six patients with human immunodeficiency virus were given foscarnet in oral solution, 4000 mg every 6 hours for 3 days, followed by a washout period for 2 days and continuous intravenous infusion of 16,000 mg/24 hr over 72 hours. After oral foscarnet, plasma concentrations were less than 33 mumol/L in four patients; two had occasional concentrations of 35 to 50 mumol/L. The extent of absorption varied between 12% and 22%. During intravenous infusion, plasma concentrations ranged between 75 and 265 mumol/L. The disposition of foscarnet was triphasic, with mean half-lives of 0.45, 3.3, and 18 hours. Excretion data suggested elimination was by tubular secretion and glomerular filtration. Renal clearance was 176 ml/min 1.73 m2. The apparent nonrenal clearance, 40 ml/min 1.73 m2, probably reflects sequestration of foscarnet into bone. Ten percent to 28% of the cumulative dose may have been deposited in bone 2 days after infusion. A slight increase in serum calcium levels and changes in serum phosphate values may reflect the uptake of foscarnet in bone. Five patients had diarrhea (oral) and two had thrombophlebitis (intravenous).

Intrapleural administration of 0.25%, 0.375%, and 0.5% bupivacaine with epinephrine after cholecystectomy.

Thirty patients who had undergone cholecystectomy (subcostal incision) were randomly allocated to three groups of ten patients each and given intrapleural injections of 20 ml 0.25% (group I), 0.375% (group II), or 0.5% (group III) bupivacaine each with added epinephrine (5 micrograms/ml). Complete pain relief was obtained within 30 minutes in all but one patient in groups I and II. Pain scores (VAS, 0-100 mm) were recorded at regular intervals and did not exceed 20 mm (mean) in any group from 30 minutes up to 4 hours. Median time interval from the intrapleural injection to administration of supplementary analgesics was 4 hours 20 minutes, 6 hours, and 7 hours 45 minutes in groups I, II, and III, respectively. The maximum plasma concentration of bupivacaine (Cmax), 0.62 (+/- 0.25 SD) microgram/ml in group I, 0.82 (+/- 0.40) microgram/ml in group II, and 1.20 (+/- 0.44) microgram/ml in group III, was significantly higher in group III than in the other groups. The time to achieve maximum plasma concentration of bupivacaine (Tmax) was approximately 15 minutes in all groups. No side effects were observed.

Remoxipride--a new potential antipsychotic drug. Pharmacological effects and pharmacokinetics following repeated oral administration in male volunteers.

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose.

Pressor response of oral tyramine in healthy men given amiflamine and placebo.

During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individual's cardiovascular pressor response. All 12 subjects "tolerated" 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure greater than 30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double-blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady-state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P less than 0.001).

The effect of adjuvant radiotherapy on the time of occurrence and prognosis of local recurrence in primary operable breast cancer.

A retrospective study was conducted of all patients with an isolated locoregional recurrence of carcinoma of the breast after modified radical mastectomy was performed with or without adjuvant radiotherapy. The findings are summarized as follows: adjuvant radiation therapy delayed the appearance of local recurrence; there was no difference in the length of time to the diagnosis of distant dissemination between the irradiated and nonirradiated patients after the treatment of locoregional relapse. 35% of the irradiated patients and 25% of the nonirradiated patients remained clinically free of disease for relatively long periods after the treatment of locoregional relapse.

Topical treatment of recurrent genital herpes infections with foscarnet.

In a double-blind study 86 patients with a total of 129 episodes of recurrent genital herpes were treated topically with 0.3% foscarnet or placebo cream. All patients considered, healing time was significantly shortened in the foscarnet group as compared to the placebo group (p less than 0.01). Subgrouped by sex, the healing time among men treated with foscarnet was significantly shortened as compared to those treated with placebo (p less than 0.002), whereas no statistical significant difference was observed among women. Foscarnet treated men with subpreputial lesions had a shorter period of ulcers (1.7 days) than placebo (3.4 days) treated men (p less than 0.02). Overall, foscarnet treatment reduced the period of redness, swelling, blisters and ulcers. Foscarnet was well tolerated, only in 1/57 patients treated was a moderate local adverse reaction recorded.

Immune status of untreated patients with Hodgkin's disease and prognosis.

In this study of 127 previously untreated adult patients with Hodgkin's disease and 167 age- and sex-matched controls, highly purified blood lymphocytes were studied for E+ receptors; their spontaneous DNA synthesis and that induced by concanavalin A, pokeweed mitogen, or purified protein derivative of tuberculin were measured as incorporation of 14C-thymidine. T-cell counts and the response to mitogens and antigen were significantly decreased in the patients, while the spontaneous lymphocyte activity was increased. Forty-nine patients had died after a mean observation time of 6 years. In these patients, there had been an increase in spontaneous DNA synthesis and a decrease in that induced by mitogens and antigen. These differences also remained significant when patients who died were compared with surviving patients in stages I-II. The 5-year survival rate of "bad immunology" patients was 30% as compared to 80% for the remainder. We suggest that these lymphocyte tests should be considered in an "immunologic staging system," which may give guidance in the future management of patients with Hodgkin's disease.

Blood T-lymphocyte functions in healthy adults in relation to age.

Blood T-lymphocyte functions were studied in 167 healthy adults (age range 19-91 years). Lymphocyte DNA synthesis induced by concanavalin A, pokeweed mitogen and PPD antigen declined with age while the spontaneous DNA synthesis remained essentially unchanged. Relative and total T-cell counts but not total lymphocyte counts were moderately decreased in elderly persons. The lymphocyte response to mitogens correlated with the PPD-induced activation in vitro. Lymphocyte and T-cell counts did not show any association with the response to mitogens and antigen. A few subjects were tested on several occasions during 2-7 years confirming a good reproducibility of the techniques employed. Thus ageing is associated with diminished number of T-cells and impairment of lymphocyte activation by T-cell mitogens and PPD antigen. The clinical importance of this general age-related T-cell deficiency remains largely unresolved.

Lymphocyte function in untreated Hodgkin's disease: an important predictor of prognosis.

One hundred and twenty seven consecutive and previously untreated patients with Hodgkin's disease (HD) (mean age 47 years) from the Stockholm area admitted to Radiumhemmet, Karolinska Hospital, were studied. The age-matched control group consisted of 167 healthy adults. Incorporation of [14C]-dT was measured on Day 1 in unstimulated monocyte-depleted lymphocyte cultures, and on Day 3 in cultures activated by PWM, ConA and PPD, T and B cells were enumerated by surface markers. The patients had significantly decreased relative and total T-cell counts, and the lymphocyte DNA synthesis induced by mitogens and PPD was severely impaired, whilst the spontaneous DNA synthesis was significantly greater than in controls. At follow-up (mean 4 years) 40 patients have died. Deceased patients showed greater spontaneous lymphocyte activation and less response to mitogen and antigen stimulation than the survivors. The 5-year survival of patients with severe lymphocyte impairment was 20%, compared to 80% for the remainder. The lymphocyte tests added prognostic information to that from clinical staging. Disregarding the lack of knowledge of the mechanisms underlying the lymphocyte impairment, we suggest that these relatively simple immunological tests should be included in the clinical evaluation of HD patients and would guide the choice of therapy.

Prognistic relevance of radiation induced immune suppression in breast carcinoma.

The extent of radiation induced immune suppression was analysed in 100 patients with carcinoma of the breast. The relative changes of lymphocyte counts and stimulations by PHA and PPD were similar in patients who differed with regard to age, size of tumour and its malignancy grade or axillary node condition. Moreover, no difference in the degree of radiation induced immune suppression existed between patients who developed recurrent disease and those who remained free of disease during a follow-up period of 4 1/2 to 7 years.

Prognostic relevance of immunologic variables in breast carcinoma.

A series of 203 consecutive patients with operable carcinoma of the breast was analysed with regard to correlations between a set of immunologic and clinical variables existing at the time of the diagnosis. No major correlations were revealed between immunologic variables on the one hand and clinical features or the course of the disease on the other. The well-known prognostic relevance of tumour size, involvement of the axilla and the histological grade of malignancy was evident.